Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways

Abstract

With the aim to provide more insight into their biology, a series of 79 liposarcomas (LS) representative of all main subtypes was analysed for chromosomal imbalances using comparative genomic hybridization. Based on the genetic data, unsupervised hierarchical clustering unveiled two main LS clusters, each with two subclusters, one comprising three subsets. The first main cluster consisted of one larger subcluster, being characterised by gains/high-level amplifications of chromosomal subregions 12q13-q15, and exclusively included well-differentiated and dedifferentiated LS. A smaller subcluster was set apart on the basis of recurrent gains of 20q13 and 8q24, and mainly comprised pleomorphic and myxoid/round cell LS. The larger subcluster was subdivided into three subsets, one with nearly exclusive overrepresentations of 12q13-q15, the second with additional frequent gains of 1q21-q24, and the third with further recurrent overrepresentations of 6q22-q24, 20q13, and 12q24 and frequent losses of 13q14-q21 and 11q22-q23. While the first subset comprised both well-differentiated and dedifferentiated LS, the second and third subsets entirely included dedifferentiated LS. The second main cluster was characterised by recurrent overrepresentations of 5p13-p15, 1q21-q24, 1p12-p21, and 17p11.2-p12 and essentially comprised pleomorphic and myxoid/round cell LS. A separation of this second main cluster into two subclusters was based on additional gains on 22q13 and losses on 1q42-q43. Genomic profiling reveals genetically distinct subsets of dedifferentiated LS, which are clearly different from pleomorphic, myxoid/round cell, and, for some subsets, from well-differentiated LS. These data indicate that dedifferentiated LS follow separate tumourigenic pathways and that genetic analysis is important to unravel these differences.

Cytogenetic and molecular cytogenetic findings in giant dedifferentiated liposarcoma of the thigh

“…Similar to WDLS, DDLS is characterized by the presence of supernumerary ring and/or giant marker chromosomes containingamplifiedgenomicsequencesinthe12q13-q15 region.Thisamplificationincludesapproximately150genes, including several of major potential relevance such as MDM2, CDK4, HMGA2, and TSPAN31 (formerly known as SAS) (16)(17)(18). MDM2isessentialforubiquitnationanddegrada-tionofthetumorsuppressorp53.MDM2 amplification is, therefore,thoughttoresultinreducedlevelsofp53.CDK4 encodes a 33-kD protein that is a key factor in the regulation of the G1-S translation of the cell cycle.…”

“…MDM2isessentialforubiquitnationanddegrada-tionofthetumorsuppressorp53.MDM2 amplification is, therefore,thoughttoresultinreducedlevelsofp53.CDK4 encodes a 33-kD protein that is a key factor in the regulation of the G1-S translation of the cell cycle. Accumulation of the CDK4-CCDN1 complex leads to phosphorylation of the RB1 In addition to the 12q13-q15 amplification, high-level amplificationsof1p32and6q23havebeenidentifiedinDDLS (5,6,17).Itisofgreatinterestthatco-amplificationsof1p32 and6q23haveneverbeenobservedinWDLS.JUN and ASK1 areup-regulatedthroughamplificationsin1p32and6q23, respectively (20,21). JUN encodes part of the activator protein transcription factor (AP-1) complex involved in cell proliferation, transformation, and apoptosis and inhibits peroxisome proliferator-activated receptor (PPAR)-γ through C/EBP beta (20,22).…”

Telomere Maintenance Mechanisms in Soft Tissue Sarcomas

“…WD/DDLS together account for 55% of all LS (40% and 15% respectively) (Conyers et al, 2011). Both WDLS and DDLS may contain a diagnostic Chr12q13-15 amplification (Rieker et al, 2010;Tap et al, 2011), although this genetic change is found more frequently in DDLS. WDLS are not typically included among the complex karyotype malignancies; however, upon dedifferentiation this tumor is included in the complex karyotype subdesignation.…”

Loss of Heterozygosity and Microsatellite Instability Are Rare in Sporadic Dedifferentiated Liposarcoma: A Study of 43 Well-Characterized Cases

“…9 Both components share a reproducible amplification of chromosome subregion 12q13-15. [10][11][12][13][14] Our group recently reported that the matched pairs of lipogenic and nonlipogenic components of dedifferentiated liposarcoma are genetically quite similar. 13 Therefore, large chromosomal gains and losses likely take place early during tumorigenesis.…”

“…Compared with other pleomorphic sarcomas, dedifferentiated liposarcoma shows few genetic changes, suggesting that early tumorigenesis does not require marked chromosomal instability. 14,27 The dedifferentiated components of liposarcomas, based on the relative enrichment of LoH, may suggest a more generalized genomic unrest during progression of this subgroup of tumors.…”